The Applicant is exploring approaches to correct the clinical manifestations of hemoglobinopathies using somatic cell gene therapy. The alpha-LCR will be coupled with human beta-globin like genes in retroviral transfer vectors. The Applicant will also take advantage of the recently identified destabilizing sequence in IVSII of the beta-globin gene to construct more efficient vectors that can transduce this gene. After the vectors have been engineered, the Applicant will test their efficacy in a number of living systems, including cell lines as well as bone marrow cells in short-term culture. The work with BM cells will test the ability of the vector to transduce pluripotent stem cells. The work will be capped off by examining the capacity for expression in thalassemic and sickle cell mouse models of the retrovirally transduced beta-globin like genes.